The activity of individual neurons that are embedded in brain circuits has critical influence on system output. In this project, we will determine how the set point for neuronal firing rate is coded in different neuron types and how it can be homeostatically maintained in the face of time, environmental change and plasticity. We have shown that firing rate set points in Drosophila central neurons, like mammalian cortical neurons, involves the activity of CaM kinases. We will use genetic techniques coupled with central neuron electrophysiology to determine how these set points are structured in both excitatory glutamatergic neurons and inhibitory GABAergic neurons. We will use transcriptional profiling to determine the output programs that are engaged when firing rates diverge from their set point in these cell types. By comparison to similar gene sets extracted from mammalian glutamatergic and GABAergic neuron types, we will determine if these output programs represent an evolutionarily conserved genomic response to firing rate perturbation. Lastly, we will perform genetic screens in Drosophila to identify new components of the core firing rate sensor. The mammalian homologs of the genes identified in these screens will be tested to determine if they are part of the homeostatic firing rate sensor in the rodent nervous system. Crustacean homologs will similarly be tested in the stomatogastric ganglion. In aggregate, these studies wdll be central to formulating an understanding of the nature of homeostasis of firing rate. The fundamental and general nature of the problem suggests that the strategies used by vertebrate and invertebrate neurons will be similar, and that a mtilti-species approach will allow us to efficiently uncover the salient features of the system. RELEVANCE (See instructions): The disregulation of excitability is central to the pathology of many developmental and acquired neurological conditions. We will use genetic methods to understand how firing rate set points are built and maintained. These studies will provided information critical to the understanding of epilepsy, chronic pain, and a host of other conditions. PROJECT/PERFORMANCE SrrE(